Prior to Sep. 11, 2001 the list of pathogens that humanity was threatened by on a day-to-day basis was relatively short and people had found means of decreasing the threat from these pathogens by developing corresponding vaccines. Nowadays this list has swelled many times from its pre-September 11 size and the threat of exposure of populations to agents from this list has grown immensely. Many vaccines are so old that they have lost their potency, while vaccines for other agents simply do not exist. The situation with the anti-BoNT vaccine is a perfect example of the former situation. As a result, the traditional vaccination approach can no longer be used to the full extent to protect society from such threats.
BoNTs are classified as Category A agents, one of the 6 highest risk threat agents for bioterrorism (2). These homologous, but serologically distinct toxins (serotypes A, B, C, D, E, F and G), specifically target neurons and, through interruption of neurotransmission, cause muscle paralysis, which leads to death from asphyxiation. It has been estimated that aerosol exposure of 100,000 individuals to the toxin, as could occur with an aerosol release over a metropolitan area, would result in 50,000 cases of illness with 30,000 fatalities (3). Such an exposure would result in 4.2 million hospital days and an estimated cost of $8.6 billion.
Pentavalent botulinum toxoid was generated over 30 years ago via chemical inactivation of native toxins of five different serotypes. This vaccine received Investigational New Drug status from the CDC (for at-risk workers), and from the United States Army's Office of the Surgeon General (for military deployment). It was stockpiled and over years was used more than 20,000 times (4). However, it was also losing its potency over the years and the CDC recently issued a notice of its discontinuation (5). The first reports of efforts to generate a new recombinant substitute for pentavalent toxoid were published almost 17 years ago (6). However, no new anti-BoNT vaccines have been approved yet. BoNTs of serotypes A and B are currently used under trade names BOTOX® and MIOBLOCK® in medicine as potent drugs and rejuvenation agents in cosmetics. Thus, it is unlikely that many people would be willing to undergo vaccination and give up the current benefits of these “miracle” drugs even if new anti-BoNT vaccines were to be developed. A more realistic strategy for raising preparedness against the threat of a bioterrorist attack would include stockpiling pathogen-specific antibodies and using them in case of an immediate threat of bioterrorist attack or soon after it.
The injection of heterologous antibodies, however, causes acute or delayed hypersensitivity reactions in 9% of cases, including serum sickness (3.7%) and anaphylactic shock (1.9%) (7). Further, application of non-human antibodies might trigger the development of an immunologic response, which will reduce or eliminate the benefit of repeating applications of such antibodies. Securing substantial quantities of human antigen-specific serums, however, may be an extremely expensive endeavor. For example, Orphan Drug human Botulism Immune Globulin has been approved by the FDA for treatment of infant botulism. It was formulated on the basis of serum obtained from human volunteers vaccinated with pentavalent botulinum toxoid. The price of this drug for treatment of one patient is $45,300.